No special risk seen for naproxen

Action Points

The risk of myocardial infarction (MI) in spondyloarthritis (SpA) is increased among current users of diclofenac, but not among users of naproxen.

Recognize that risks for MI are increased among patients with rheumatoid arthritis and SpA, possibly because of systemic inflammation, conventional cardiovascular (CV) risk factors, and use of medications that may contribute to the risk.

The risk of myocardial infarction (MI) was elevated among patients with spondyloarthritis (SpA) who used diclofenac, though not among those treated with naproxen, a nested case-control study found.

In a cohort of patients with SpA, the adjusted odds ratio for MI was 3.32 (95% CI 1.57-7.03) among those currently taking diclofenac when compared with those whose exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) was at least a year in the past (remote use), according to Maureen Dubreuil, MD, of Boston University School of Medicine, and colleagues.

In contrast, current use of naproxen was associated with an adjusted odds ratio of 1.19 (95% CI 0.53-2.68), which was not significantly increased compared with remote NSAID use, the researchers reported in Annals of the Rheumatic Diseases.

"These results suggest that diclofenac use contributes to risk of MI in patients with SpA, and has the important implication for patients with SpA and clinicians that MIs could be prevented through preferential use of naproxen."

Risks for MI are increased among patients with rheumatoid arthritis and SpA -- possibly because of systemic inflammation, conventional cardiovascular (CV) risk factors, and use of medications that may contribute to risk, such as NSAIDs. The selective cyclooxygenase-2 inhibitors originally were implicated and some were removed from the market, but some of the currently available nonselective NSAIDs also have been linked with CV events.

For instance, a meta-analysis found a 41% increase in major vascular events with high-dose diclofenac and a possible (though not statistically significant) increase for high-dose ibuprofen among individuals without CV disease (RR 1.44, 95% CI 0.89-2.33). Naproxen was not associated with an increased risk in this population (RR 0.93, 95% CI 0.69-1.27).

While the association between CV risk and NSAID use has been scrutinized in the general population, risks among patients with SpA have not been widely examined, despite their frequent use of NSAIDs as first-line treatment for pain and stiffness. These drugs might either increase the risk, as in the general population, or decrease the risk by reducing systemic inflammation, the researchers noted.

To examine these possibilities, the team analyzed data from The Health Improvement Network (THIN) for the years 1994 to 2015. THIN includes prospectively collected data on more than 11 million people in the U.K.

From this database, the researchers identified 8,140 patients with SpA, 115 of whom had MI diagnoses, and 455 SpA controls without MI. For an additional control, the researchers also identified 244,339 individuals with osteoarthritis (OA), which is not generally associated with high levels of systemic inflammation. From this group, there were 6,287 cases of MI and 25,164 matched controls.

In the SpA cohort, mean age was 63 and 30% were women, while in the OA cohort, mean age was 73 and almost half were women.

Overall, the MI cases had more traditional CV risk factors and more frequently were receiving medications for hypertension and diabetes.

A total of 25 SpA patients were current diclofenac users, meaning that they had a prescription within the past 180 days, and 14 were current naproxen users, while 39 were remote NSAID users.

In the OA group, 843 of the MI cases were current diclofenac users and 339 were current naproxen users, while 3,197 were remote NSAID users. Most diclofenac users were on a daily dose of 100 mg or more, and for naproxen, the most common daily dose was 1,000 mg.

The researchers also calculated odds ratios for MI among SpA patients currently on other NSAIDs, such as celecoxib, meloxicam, and indomethacin, and found no increased risk (OR 1.23, 95% CI 0.61-2.46).

For patients with OA, there again was an elevated risk of MI with current diclofenac use (OR 1.26, 95% CI 1.14-1.39) and with other NSAID use (OR 1.17, 95% CI 1.07-1.28), but no risk was seen for naproxen use (OR 0.98, 95% CI 0.85-1.13).

"Using the results from the primary analysis, the ratio of adjusted ORs for current diclofenac (OA as the referent) was 2.64 (95% CI 1.24-5.58), suggesting an interaction between the underlying form of arthritis (SpA versus OA) and MI risk with diclofenac use, meaning that MI risk differed between the two groups," the authors explained.

Limitations of the study, the researchers said, included the possibility of disease misclassification and inconsistent NSAID use, as well as the possibility of confounding by indication. Strengths included the large population and the "real-world" use.

"If confirmed in other large SpA datasets, these findings may motivate a change in practice guidelines to recommend naproxen as the preferred first-line NSAID in SpA," the investigators concluded.

The study was supported by the Arthritis Foundation and the National Institutes of Health.

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